Received 6/18/97, Accepted 7/22/97

Most of the research efforts on retroviruses over the past 10-15 years have focused on the mechanisms of disease production by these pathogens. Now it is time to explore the mechanisms by which infected hosts protect themselves and the potential factors which adversely effect the anti-retroviral 'molecular immunity'. If one assumes that evolution has created some sort of intracellular protective mechanisms to specifically battle retroviruses—different from humoral or cell-mediated immunity—then many of the previously anomalous phenomena reported by various investigators could be explained on the basis of this alternative hypothesis. For example, it can explain why SlVagm, which has the same overall genomic organization as the other lentiviruses, causes no known disease in its native host, the African green monkey, but does cause AIDS-like disease in other species. Similarly, it can explain why the SIVsm causes no significant disease in its natural host the sooty mangabey and yet causes an AlDS-like illness in experimentally infected, naive, rhesus macaques and cynomolgus monkeys. While there are genomic differences between the rapidly-fatal variant of SlVsm and other SlVsm subtypes, the differences fail to clearly define the pathogenic moiety of this virus (107). Similarly, in the oncoviral family of complex retroviruses, there is HTLV-I, for example, which if acquired in infancy in southeast Japan, leads to leukemia (ATLL) in a small minority of the population, while in the much larger majority, the virus remains clinically latent throughout life (108). In certain Caribbean populations, however, infection with this retrovirus tends to occur later in life, and among this population, HTLV-I leads primarily to a neuropathic disease (109). HTLV-II, in contrast, which is endemic in certain isolated populations throughout the world causes no known disease (110). HIV-1, which has devastated certain human populations, is most closely related to SIVcpz which appears to cause no disease in either naturally-infected or experimentally-infected chimpanzees. What is becoming increasingly clear is that the final disease potential of retroviruses lies in the complex interaction of the retrovirus with the infected host. Perhaps the survival of the host depends on the rapid development of intracellular defenses that are able to "prime" the majority of target cells with the appropriate defenses, outracing the pathogenic effects of the retroviruses. In the primates and humans, we hypothesize that the defenses are already in place against retroviruses and it may be the environmental factors which can tilt the balance in favor of the pathogens (see below).